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Immunosenescence and Lung Transplantation: What Does It Mean to Be Old?


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Oveimar De La Cruz, MD
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
oveimarc@hotmail.com



"Anyone who stops learning is old, whether at twenty or eighty. Anyone who keeps learning stays young. The greatest thing in life is to keep your mind young". — Henry Ford


Functional changes in the immune system associated with aging are collectively referred to as immunosenescence. This phenomenon correlates with fatal infections, increased risk of cancer, high levels of autoantibodies, decreased response to vaccines and, in transplant recipients, lower rates of rejection [1,2,3]. Phenotypically, a constellation of modifications occurs at different levels:

Ultimately, immunosenescence occurs due to a dysregulation of the intracellular pathway transduction and interaction among different cell lines (neutrophils, mononuclear cells, dendritic cells, macrophages, NKs). As the nature of the immune system is to dynamically "learn" and defend against different noxious challenges, its senescence equates to the inability to keep up with the plasticity of younger times.

Immunosenescence is especially relevant to transplantation. The number of solid organ transplant (SOT) recipients older than 65 years has increased consistently in the last 2 decades, with outcomes that are acceptable when compared to younger patients. Nevertheless, infection remains the number one cause of morbidity and mortality among elderly SOT recipients.

The 2006 ISHLT Pulmonary Scientific Council Consensus Report suggests a cutoff age of 65 for lung transplantation. This has been the practice at many institutions, mainly due to reported poor outcomes in an earlier era of lung transplantation [4]. Since implementation of LAS (Lung Allocation Score) in 2005, data has collectively demonstrated that appropriate candidate selection leads to favorable post-transplant outcomes in elderly recipients [5,6]. Vadnekar et al showed that although the >65 years lung transplant population had fewer rates of rejection, they tended to suffer from an increased proportion of infectious complications and malignancy [7]. These observations suggest that a complex influence of anti-rejection regimens on the senescent immune system of older recipients exist [1]. In fact, the intricate balance of anti-rejection drugs and the immune system is one of the greatest challenges in transplantation medicine, a challenge that is even more important in the elderly since immunosuppressant regimens are not adjusted based on age.

In addition, during the early post transplant period, morbidity and mortality from bacterial infections suggests that there are functional gaps related to the innate immune system. The key role of this compartment is also a focus of attention in lung allografts. Lung allografts are exposed directly to the environment and as such they face continuous non-specific antigenic challenges ranging from containment of the normal microbial flora to ischemic reperfusion injury. Its implication on chronic lung allograft rejection and tolerance is being increasingly discussed as well [8]. Clinical biomarkers are not available to elucidate these conundrums.

In this sense, a critical barrier keeping clinicians from preventing infections, malignancy and allograft rejection in older lung transplant recipients is the scarce information on underlying immune dysfunction related to age. We also lack the knowledge of how different compartments of the immune system and cytokine dynamics are modeled by antirejection medications and its variation through different ages. The role of specific infections by immunomodulating viruses that are prevalent in lung transplant recipients, such as CMV, EBV and other herpes viruses, complicates this puzzling picture even more.

Lung transplantation at extremes of age is becoming a common scenario with exciting clinical and research challenges. Development of novel diagnostic tests to assess infection risk, and of therapies to bolster the immune system, is needed if we aim to take better care of this elderly transplant recipient population. Likewise, more accurate bioassays are needed to monitor net state of immune response, to guide clinicians on pharmacologic manipulations, and to help the immune system refresh what it knew well years before.

In summary:


Disclosure Statement: the author has no conflicts of interest to report.


References:

  1. Heinbokel T, Hock K, Liu G, et al. Impact of immunosenescence on transplant outcome. Transpl Int. 2012 Nov 29. doi: 10.1111/tri.12013. [Epub ahead of print] PubMed PMID: 23190423.
  2. High KP, D'Aquila RT, Fuldner RA et al. Workshop on immunizations in older adults: identifying future research agendas. J Am Geriatr Soc. 2010 Apr;58(4):765-76. doi: 10.1111/j.1532-5415.2010.02772.x. PubMed PMID: 20398161.
  3. Keith DS. Transplantation in the elderly patient. Clin Geriatr Med. 2013 Aug;29(3):707-19. doi: 10.1016/j.cger.2013.05.010. PubMed PMID: 23849015.
  4. Orens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update—a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006 Jul;25(7):745-55. PubMed PMID: 16818116.
  5. Kilic A, Merlo CA, et al. (2012). "Lung transplantation in patients 70 years old or older: have outcomes changed after implementation of the lung allocation score?" J Thorac Cardiovasc Surg 144(5): 1133-1138.
  6. Smith PW, Wang H, et al. (2006). "Lung transplantation in patients 60 years and older: results, complications, and outcomes." Ann Thorac Surg 82(5): 1835-1841; discussion 1841
  7. Vadnerkar A, Toyoda Y, et al. (2011). "Age-specific complications among lung transplant recipients 60 years and older." J Heart Lung Transplant 30(3): 273-281.
  8. Kreisel D, Goldstein DR. Innate immunity and organ transplantation: focus on lung transplantation. Transpl Int. 2013 Jan;26(1):2-10. doi:10.1111/j.1432-2277.2012.01549.x. Epub 2012 Aug 21. Review. PubMed PMID: 22909350; PubMed Central PMCID: PMC3505267.



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